Indoles

ABSTRACT

The present invention is concerned with novel indol-2-yl-carbonyl-piperidin-benzoimidazolon and indol-2-yl-carbonyl-piperidin-benzoxazolon derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use for the treatment of anxiety and depressive disorders and other diseases. In particular, the present invention concerns compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 11 , X and Y are as defined in the specification.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06125663.2, filed Dec. 8, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8). The V1areceptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxious behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxious behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann NY Acad Sci 897: 198-211). In the periphery it inducesthe contraction of vascular smooth muscles and chronic inhibition of theV1a receptor improves hemodynamic parameters in myocardial infarctedrats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). “Chronicvasopressin V(1A) but not V(2) receptor antagonism prevents heartfailure in chronically infarcted rats.” Eur J Pharmacol 449(1-2):135-41).

SUMMARY OF THE INVENTION

The present invention provides novelindol-2-yl-carbonyl-piperidin-benzoimidazolon andindol-2-yl-carbonyl-piperidin-benzoxazolon derivatives, theirmanufacture, pharmaceutical compositions containing them. The compoundsof formula (I) are V1a receptor modulators, and in particular are V1areceptor antagonists. The present invention provides methods for thetreatment of such conditions as dysmenorrhea, hypertension, chronicheart failure, inappropriate secretion of vasopressin, liver cirrhosis,nephrotic syndrome, obsessive compulsive disorder, anxiety anddepressive disorders. The preferred indications with regard to thepresent invention are the treatment of anxiety and depressive disorders.

In particular, the present invention provides compounds of formula (I)

wherein

-   X and Y are selected from the combinations of:-   X is NR⁷and Y is C═O,-   X is CH₂ and Y is C═O,-   X—Y is N═N, and-   X is O and Y is C═O;-   R¹ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH, or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R³ is hydrogen, halo, or C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;    -   or R⁴ and R⁵ are bound together to form a ring with the benzo        moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),    -   —O-benzyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to        6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to        6-membered cycloalkyl,        -   each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,        -   —C(O)—(CH₂)_(n)—O—, or        -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁₋₆-alkoxy;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-NR^(k)R^(l),        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g) and R^(h) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e)        -   wherein R^(e) is selected from the group of            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   or R^(c) and R^(d), or R^(g) and R^(h) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;    -   or R^(c) and R^(d), or R^(g) and R^(h) together with the        nitrogen to which they are bound form isoindole-1,3-dione;-   R^(f) is selected from    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thetext or in the examples, or by methods known in the art.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

In the present description, the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated hydrocarbon radical. The term “C₁₋₆-alkyl” denotes a saturatedstraight- or branched-chain hydrocarbon group containing from 1 to 6carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, the isomeric pentyls and the like. A preferredsub-group of C₁₋₆-alkyl is C₁₋₄-alkyl, i.e. with 1-4 carbon atoms.

In the present invention, the term “alkylene” refers to a linear orbranched saturated divalent hydrocarbon radical. In particular,“C₁₋₆-alkylene” means a linear saturated divalent hydrocarbon radical ofone to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g. methylene, ethylene,2,2-dimethylethylene, n-propylene, 2-methylpropylene, and the like.

In the present description, the terms “alkoxy” and “C₁₋₆-alkoxy” referto the group R′—O—, wherein R′ is C₁₋₆-alkyl as defined above. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy and the like. A preferred sub-group ofC₁₋₆-alkoxy, and still more preferred alkoxy groups are methoxy and/orethoxy.

In the present description, the term “thioalkyl” and “C₁₋₆-thioalkyl”refers to the group R′—S—, wherein R′ is C₁₋₆-alkyl as defined above.

The terms “C₁₋₆-hydroxyalkyl” and “C₁₋₆-alkyl substituted by OH” denotea C₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a hydroxyl group.

The terms “C₁₋₆-cyanoalkyl” and “C₁₋₆-alkyl substituted by CN” denote aC₁₋₆-alkyl group as defined above wherein at least one of the hydrogenatoms of the alkyl group is replaced by a CN group.

The terms “halo” and “halogen” refer to fluorine (F), chlorine (Cl),bromine (Br) and iodine (I) with fluorine, chlorine and bromine beingpreferred.

The term “halo-C₁₋₆-alkyl” denotes a C₁₋₆-alkyl group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Examples of halo-C₁₋₆-alkyl include but are not limited tomethyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) aswell as those groups specifically illustrated by the examples hereinbelow. Among the preferred halo-C₁₋₆-alkyl groups are difluoro- ortrifluoro-methyl or -ethyl.

The term “halo-C₁₋₆-alkoxy” denotes a C₁₋₆-alkoxy group as defined abovewherein at least one of the hydrogen atoms of the alkyl group isreplaced by a halogen atom, preferably fluoro or chloro, most preferablyfluoro. Among the preferred halogenated alkoxy groups are difluoro- ortrifluoro-methoxy or -ethoxy.

The term “C₂₋₁₂-alkenyl”, alone or in combination, denotes astraight-chain or branched hydrocarbon residue of 2 to 12 carbon atomscomprising at least one double bond. A preferred sub-group ofC₂₋₁₂-alkenyl is C₂₋₆-alkenyl. Examples of the preferred alkenyl groupsare ethenyl, propen-1-yl, propen-2-yl(allyl), buten-1-yl, buten-2-yl,buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl,hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as wellas those specifically illustrated by the examples herein below.

The term “5 or 6 membered heteroaryl” means an aromatic ring of 5 or 6ring atoms as ring members containing one, two, or three ringheteroatoms selected from N, O, and S, the rest being carbon atoms. 5 or6 membered heteroaryl can optionally be substituted with one, two, threeor four substituents, wherein each substituent may independently beselected from the group consisting of hydroxy, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-thioalkyl, halo, cyano, nitro, halo-C₁₋ ₆-alkyl, C₁₋₆-hydroxyalkyl,C₁₋₆-alkoxycarbonyl, amino, C₁₋₆-alkylamino, di(C₁₋₆)alkylamino,aminocarbonyl, and carbonylamino, unless otherwise specificallyindicated. Preferred substituents are halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, optionally substituted oxazolyl, optionally substitutedthiazolyl, optionally substituted pyrazinyl, optionally substitutedpyrrolyl, optionally substituted pyrazinyl, optionally substitutedpyridinyl, optionally substituted pyrimidinyl, optionally substitutedfuranyl, and those which are specifically exemplified herein.

The term “heterocycloalkyl” means a monovalent saturated moiety,consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ringmembers, including one, two, or three heteroatoms chosen from nitrogen,oxygen or sulfur, the rest being carbon atoms. 3 to 7 memberedheterocycloalkyl can optionally be substituted with one, two, three orfour substituents, wherein each substituent is independently hydroxy,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, cyano, nitro,halo-C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-alkoxycarbonyl, amino,C₁₋₆-alkylamino, di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino,unless otherwise specifically indicated.

Preferred substituents are halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano. Examples of heterocyclicmoieties include, but are not limited to, optionally substitutedtetrahydro-furanyl, optionally substituted piperidinyl, optionallysubstituted pyrrolidinyl, optionally substituted morpholinyl, optionallysubstituted piperazinyl, and the like or those which are specificallyexemplified herein.

The term “heterocycle” in the definition “R^(a) and R^(b), R^(c) andR^(d), R^(g) and R^(h), R^(i) and R^(j), together with the nitrogen towhich they are bound form a five- or six-membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur” means either heterocycloalkyl or heteroaryl in the above-givensense which may optionally be substituted as described above.Preferably, the “heterocycle” may optionally be substituted with one,two or three substituents selected from halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, and cyano. Preferredheterocycles are piperazine, N-methylpiperazine, morpholin, piperidineand pyrrolidine.

The term “one or more” substituents preferably means one, two or threesubstituents per ring.

The term “cycloalkyl” means a cycloalkyl group containing 3 to 6 carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Cycloalkyl containing 3 to 4 carbon atoms are the most preferred.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salt” embraces saltswith inorganic and organic acids, such as hydrochloric acid, nitricacid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaricacid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

In detail, the present invention relates to compounds of the generalformula (I)

wherein

-   X and Y are selected from the combinations of:-   X is NR⁷and Y is C═O,-   X is CH₂ and Y is C═O,-   X—Y is N═N, and-   X is O and Y is C═O;-   R¹ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH, or    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b);-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano, or    -   phenyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;-   R³ is hydrogen, halo, or C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),    -   —O-benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to        6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to        6-membered cycloalkyl,        -   each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,        -   —C(O)—(CH₂)_(n)—O—, or        -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁₋₆-alkoxy;-   R^(a), R^(b), R^(i) and R^(j) are each independently    -   hydrogen,    -   C₁₋₆-alkyl, or    -   —(C₁₋₆-alkylene)-NR^(k)R^(l),        -   wherein R^(k) and R^(l) are each independently hydrogen or            C₁₋₆-alkyl,    -   or R^(a) and R^(b), or R^(i) and R^(j) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;-   R^(c), R^(d), R^(g) and R^(h) are each independently    -   hydrogen,    -   C₁₋₆-alkyl,    -   —C(O)R^(e), or —S(O)₂R^(e)        -   wherein R^(e) is selected from the group of            -   hydrogen,            -   C₁₋₆-alkyl, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   or R^(c) and R^(d), or R^(g) and R^(h) together with the        nitrogen to which they are bound form a five or six membered        heterocycle comprising one or two heteroatoms selected from the        group of nitrogen, oxygen and sulfur;    -   or R^(c) and R^(d), or R^(g) and R^(h) together with the        nitrogen to which they are bound form isoindole-1,3-dione;-   R^(f) is selected from    -   hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy; and    -   phenyl, optionally substituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;        or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(g) and R^(h) together with the nitrogen towhich they are bound may form piperazine, 4-(C₁₋₆-alkyl)-piperazine,4-methylpiperazine, morpholine, piperidine or pyrrolidine.

In certain embodiments of the invention, R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(g) and R^(h) together with the nitrogen towhich they are bound may form 4-methylpiperazine, or morpholine.

In certain embodiments of the invention, wherein R^(m) is a 5- to6-membered heteroaryl, the preferred heteroaryl is selected from thegroup consisting of pyridine, pyrimidine, pyrazine, pyridazine,imidazole, pyrazole, oxazole, and isoxazole.

In embodiments of the invention, wherein R^(m) is a 4- to 6-memberedheterocycloalkyl, the preferred heterocycloalkyl is selected from thegroup consisting of pyrrolidine, oxethane, tetrahydropyrane, piperidine,morpholine, and piperazine.

In certain embodiments of the invention, R¹ is hydrogen or C₁₋₆-alkyl,optionally substituted by CN or OH.

In certain embodiments of the invention,

-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e)                -   wherein R^(e) is selected from the group of                    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano, or        -   R^(c) and R^(d) together with the nitrogen to which they are            bound form isoindole-1,3-dione,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   wherein R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano;    -   benzyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano,    -   phenyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano.

In certain embodiments of the invention, R³ is hydrogen or halo.

In certain embodiments of the invention,

-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl, or    -   C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2.

In certain embodiments of the invention,

-   R⁵ is hydrogen, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2.

In certain embodiments of the invention,

-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h)        -   wherein R^(g) and R^(h) are each independently selected from            hydrogen and C₁₋₆-alkyl;        -   or wherein R^(g) and R^(h) together with the nitrogen to            which they are bound form a five or six membered heterocycle            comprising one or two heteroatoms selected from the group of            nitrogen, oxygen and sulfur;    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j)        -   wherein R^(i) and R^(j) are each independently            -   hydrogen;            -   C₁₋₆-alkyl;            -   —(C₁₋₆-alkylene)-NR^(k)R^(l);                -   wherein R^(k) and R^(l) are each independently                    hydrogen or C₁₋₆-alkyl;        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur;    -   —O-benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;    -   nitro;    -   halo;    -   cyano;    -   C₁₋₆-alkoxy;    -   halo-C₁₋₆-alkoxy;    -   halo-C₁₋₆-alkyl;    -   —(C₁₋₆-alkylene)-C(O)R^(f);        -   wherein R^(f) is selected from            -   hydrogen;            -   C₁₋₆-alkyl;            -   C₁₋₆-alkoxy; and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,    -   phenyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano;    -   —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to        6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to        6-membered cycloalkyl,        -   each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano; or-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,        -   —C(O)—(CH₂)_(n)—O—, or        -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;

In certain embodiments of the invention,

-   R⁶is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —O-benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶— is —O—(CH₂)_(n)—C(O)—, or —C(O)—(CH₂)_(n)—O— wherein n        is 1 or 2.

In certain embodiments, R⁷ is hydrogen.

In certain embodiments all R⁸ to R¹¹ are hydrogen.

In certain embodiments, R⁸ to R¹¹ are independently hydrogen or halo.

In certain embodiments, R⁹ is fluoro, and R⁸, R¹⁰ and R¹¹ are hydrogen.

In certain embodiments, R⁸, R⁹ and R¹¹ are hydrogen and R¹⁰ is bromo.

In certain embodiments, R⁸ to R¹¹ are independently hydrogen or methyl.

In certain embodiments, R⁸ to R¹⁰ are hydrogen and R¹¹ is methyl.

In certain embodiments of the invention, X is NR⁷ and Y is C═O, i.e.compounds of formula (Ia)

wherein R¹ to R¹¹ are as defined herein above.

In certain embodiments of the invention, X is CH₂ and Y is C═O, i.e.compounds of formula (Ib)

wherein R¹ to R⁶ and R⁸ to R¹¹ are as defined herein above.

In certain embodiments of the invention, X—Y is N═N, i.e. compounds offormula (Ic)

wherein R¹ to R⁶ and R⁸ to R¹¹ are as defined herein above.

In certain embodiments of the invention, X is O and Y is C═O, i.e.compounds of formula (Id)

wherein R¹ to R⁶ and R⁸ to R¹¹ are as defined herein above.

In certain embodiments of the invention, R¹ to R⁶ are not all hydrogen.

In certain embodiments of the invention, R¹ to R¹¹ are not all hydrogen.

The invention further encompasses an embodiment with the compound offormula (I),

wherein

-   X is NR⁷ and Y is C═O; or-   X is CH₂ and Y is C═O; or-   X—Y is N═N;-   R¹ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-C(O)—NR^(a)R^(b),        -   wherein R^(a) and R^(b) are each independently hydrogen or            C₁₋₆-alkyl;-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e),                -   wherein R^(e) is selected from                -    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano;        -   or R^(c) and R^(d) together with the nitrogen to which they            are bound form isoindole-1,3-dione,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   wherein R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,    -   benzyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   phenyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano;-   R³ is hydrogen, halo, or C₁₋₆-alkyl;-   R⁴ is hydrogen,    -   halo,    -   C₁₋₆-alkyl,    -   halo-C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy, or    -   —O—C₂₋₁₀-alkenyl;-   R⁵ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —(C₁₋₆-alkylene)-NR^(g)R^(h),        -   wherein R^(g) and R^(h) are each independently selected from            hydrogen and C₁₋₆-alkyl;        -   or wherein R^(g) and R^(h) together with the nitrogen to            which they are bound form a five or six membered heterocycle            comprising one or two heteroatoms selected from the group of            nitrogen, oxygen and sulfur,    -   —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j),        -   wherein R^(i) and R^(j) are each independently            -   hydrogen,            -   C₁₋₆-alkyl,            -   —(C₁₋₆-alkylene)-NR^(k)R^(l),                -   wherein R^(k) and R^(l) are each independently                    hydrogen or C₁₋₆-alkyl;        -   or R^(i) and R^(j) together with the nitrogen to which they            are bound form a five or six membered heterocycle comprising            one or two heteroatoms selected from the group of nitrogen,            oxygen and sulfur,    -   —O-benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   nitro,    -   halo,    -   cyano,    -   C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkoxy,    -   halo-C₁₋₆-alkyl,    -   —(C₁₋₆-alkylene)-C(O)R^(f),    -   phenyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano,    -   —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to        6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to        6-membered cycloalkyl,        -   each optionally substituted by one or more halo,            halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,            nitro, or cyano;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—,    -   —C(O)—(CH₂)_(n)—O—, or    -   —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁷ is hydrogen or C₁₋₆-alkyl;-   R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo,    C₁₋₆-alkyl or halo-C₁₋₆-alkyl.

The invention further encompasses an embodiment with the compound offormula (I),

wherein

-   X is NR⁷ and Y is C═O;-   X is CH₂ and Y is C═O;-   X—Y is N═N;-   X is O and Y is C═O;-   R¹ is hydrogen or C₁₋₆-alkyl, optionally substituted by CN or OH;-   R² is hydrogen,    -   C₁₋₆-alkyl,    -   C₁₋₆-alkoxy,    -   —(C₁₋₆-alkylene)-NR^(c)R^(d),        -   wherein R^(c) and R^(d) are each independently            -   hydrogen,            -   —C(O)R^(e), or —S(O)₂R^(e),                -   wherein R^(e) is selected from                -    hydrogen,                -    C₁₋₆-alkyl, and                -    phenyl, optionally substituted by one or more halo,                    halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                    halo-C₁₋₆-alkoxy, nitro, or cyano;        -   or R^(c) and R^(d) together with the nitrogen to which they            are bound form isoindole-1,3-dione,    -   —(C₁₋₆-alkylene)-C(O)R^(f),        -   wherein R^(f) is selected from            -   hydrogen,            -   C₁₋₆-alkyl,            -   C₁₋₆-alkoxy, and            -   phenyl, optionally substituted by one or more halo,                halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,                halo-C₁₋₆-alkoxy, nitro, or cyano,    -   benzyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or    -   phenyl, optionally subsitituted by halo, halo-C₁₋₆-alkyl,        C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano;-   R³ is hydrogen, halo, or C₁₋₆-alkyl;-   R⁴ is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   R⁵ is hydrogen, C₁₋₆-alkyl, or C₁₋₆-alkoxy;-   or R⁴ and R⁵ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2;-   R⁶ is hydrogen,    -   C₁₋₆-alkyl, optionally substituted by CN or OH,    -   —O-benzyl, optionally subsitituted by one or more halo,        halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,        nitro, or cyano; or    -   nitro;-   or R⁵ and R⁶ are bound together to form a ring with the benzo    moiety, wherein    -   —R⁵—R⁶— is —O—(CH₂)_(n)—C(O)—; or —C(O)—(CH₂)_(n)—O— and n is 1        or 2;-   R⁷ is hydrogen;-   R⁸, R⁹, R¹⁰, and R¹¹ are each hydrogen.

Preferred compounds of the invention are those as shown in the examplesabove.

More preferred compounds of formula Ia are

-   {5-Bromo-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile,-   N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide,-   4-Fluoro-N-{5-methyl-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-benzamide,-   {2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-acetic    acid ethyl ester,-   1-[1-(7-Benzyloxy-1H-indole-2-carbonyl)-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one,-   {5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile,    or-   {5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-7-yl}-acetonitrile.

A preferred compound of formula Ib is

-   1-[1-(5-Chloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one.

A preferred compound of formula Ic is

-   (4-Benzotriazol-1-yl-piperidin-1-yl)-(5-chloro-1H-indol-2-yl)-methanone.

The invention also encompasses methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety and depressive disorders which comprisesadministering a therapeutically effective amount of a compound offormula (I), (Ia), (Ib), (Ic), or (Id).

The invention also encompasses a pharmaceutical composition comprising acompound of formula (I), (Ia), (Ib), (Ic), or (Id) and apharmaceutically acceptable carrier. The pharmaceutical composition canfurther comprise at least one pharmaceutically acceptable excipient.

In a certain embodiment, the compound of the invention can bemanufactured according to a process comprising reacting a compound offormula (II):

with an amine of formula 1

wherein R¹ to R⁶ and R⁸ to R¹¹ and X and Y are as defined above.

In a certain embodiment, the compound of the invention can bemanufactured according to a process comprising reacting a compound offormula (I-1):

with an electrophile of formula R¹-hal, to give a compound of generalformula (I) as defined herein above.

The synthesis of compounds of formula (I) will be described in moredetail below and in the examples.

wherein A is:

wherein

-   X and Y are selected from the combinations of:-   X is NR⁷ and Y is C═O,-   X is CH₂and Y is C═O,-   X—Y is N═N, and-   X is O and Y is C═O

Compounds of formula (I) can be prepared via an amide coupling betweenan indole 2-carboxylic acid (II) and a compound of formula (A-H),wherein A is defined as hereinabove. The usual reagents and protocolsknown in the art can be used to effect the amide coupling. Indole2-carboxylic acids (II) are either commercially available or readilyprepared using procedures described hereinafter. The compounds offormula (A-H) are either commercially available or prepared usingmethods known in the art starting from commercially available materials.General scheme A is hereinafter further illustrated with generalprocedure I.

General Procedure I: Amide Coupling:

To a stirred solution of an indole-2-carboxylic acid derivative (1 mmol)in 10 ml CH₂Cl₂ were added (1.3 mmol) EDC, (1.3 mmol) HOBt, (1.3 mmol)Et₃N and (1 mmol) of the amine derivative A-H. The mixture was stirredovernight at RT and then poured onto water and extracted with CH₂Cl₂.The combined organic phases were dried over Na₂SO₄ and concentrated invacuo. Flash chromatography or preparative HPLC afforded the titlecompound.

Compounds of formula (I-2) (compounds of formula (I) wherein R¹ isdifferent from H), can be prepared by alkylation of the indolederivative of formula (I-1), with an electrophile of formula R¹-hal(commercially available, wherein hal is halo, preferably Cl or Br) usingstandard procedures. Derivatives (I-1) are prepared using the amidecoupling as described in the general scheme A.

Substituted indole 2-carboxylic acids can be prepared according to thegeneral scheme C. Indoles V are obtained by a Fischer indole synthesisfrom an aryl hydrazine III and a α-ketoester IV. Saponification gives anacid of formula II-a. Alternatively, Boc protection of the indolenitrogen gives VI. Selective bromination of the methyl group in the7-position of the indole using NBS affords VII. Subsequent nucleophilicsubstitution of 7-bromomethyl indole intermediate VII with NaCN or asecondary amine yields intermediates VIII and IX, respectively. AfterN-deprotection and saponification of the ester moiety, the correspondingcarboxylics acids II-b and II-c are obtained.

Abbreviations used:

-   NBS=N-Bromosuccinimide-   Boc=tert-buthoxycarbonyl

V1a Activity Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells were resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)), homogenized withPolytron for 1 min, and sonicated on ice for 2×2 minutes at 80%intensity (Vibracell sonicator). The preparation was centrifuged 20 minat 500 g at 4° C., the pellet was discarded, and the supernatantcentrifuged 1 hour at 43,000 g at 4° C. (19,000 rpm). The pellet wasresuspended in 12.5 ml Lysis buffer+12.5 ml Sucrose 20% and homogenizedusing a Polytron for 1-2 min. The protein concentration was determinedby the Bradford method and aliquots were stored at −80° C. until use.For binding studies, 60 mg Yttrium silicate SPA beads (Amersham) weremixed with an aliquot of membrane in binding buffer (50 mM Tris, 120 mMNaCl, 5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing. 50ul of bead/membrane mixture was then added to each well of a 96 wellplate, followed by 50 ul of 4 nM 3H-Vasopressin (American RadiolabeledChemicals). For total binding measurement 100 ul of binding buffer wereadded to the respective wells, for non-specific binding 100 ul of 8.4 mMcold vasopressin were added, and for compound testing 100 ul of a serialdilution of each compound in 2% DMSO were added. The plate was incubated1 h at room temperature, centrifuged 1 min at 1000 g and counted on aPackard Top-Count. Non-specific binding counts were subtracted from eachwell and data was normalized to the maximum specific binding set at100%. To calculate an IC 50, the curve was fitted using a non-linearregression model (XLfit) and the Ki was calculated using theCheng-Prussoff equation.

Example pKi 3 7.92 10 7.7 11 7.4 14 7.38 37 7.66 45 7.495 46 7.45 477.19 48 6.415

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example compounds of formulaI or IA, and their pharmaceutically acceptable acid addition salts, anda pharmaceutically acceptable carrier. Such pharmaceutical compositionscan be in the form of tablets, coated tablets, dragees, hard and softgelatin capsules, solutions, emulsions or suspensions. Thepharmaceutical compositions also can be in the form of suppositories orinjectable solutions.

The pharmaceutical compounds of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts etc canbe used as such excipients e.g. for tablets, dragees and hard gelatincapsules. Suitable excipients for soft gelatin capsules are e.g.vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitableexcipients for the manufacture of solutions and syrups are e.g. water,polyols, saccharose, invert sugar, glucose etc. Suitable excipients forinjection solutions are e.g. water, alcohols, polyols, glycerol,vegetable oils etc. Suitable excipients for suppositories are e.g.natural or hardened oils, waxes, fats, semi-liquid or liquid polyolsetc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula (I) should be appropriate, although theabove upper limit can also be exceeded when necessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

EXAMPLE A

Tablets of the following composition can be manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

EXAMPLE B

Capsules of the following composition can be manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch can be firstly mixed in amixer and then in a comminuting machine. The mixture then can bereturned to the mixer, the talc added thereto, and mixed thoroughly. Themixture can be filled by machine into hard gelatin capsules.

EXAMPLE C

Suppositories of the following composition can be manufactured:

mg/supp. Active substance  15 Suppository mass 1285 Total 1300

The suppository mass can be melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered activesubstance can be added thereto and stirred until it has dispersedcompletely. The mixture can be poured into suppository moulds ofsuitable size, left to cool; the suppositories can then be removed fromthe moulds and packed individually in wax paper or metal foil.

In the following, the synthesis of compounds of formula (I) is furtherexemplified. The compounds of formula I may be prepared in accordancewith the process variants as described above. The starting materialsdescribed in the Example section are either commercially available orotherwise known or derived from the chemical literature, for instance ascited below, or may be prepared as described in the Examples section.

EXAMPLES

General Procedure I—Amide coupling:

To a 0.1 M stirred solution of an indole-2-carboxylic acid derivative oftype (II) in CH₂Cl₂ are added EDC (1.3 eq), HOBt (1.3 eq), Et₃N (1.3 eq)and the amine derivative (A-H, as defined above, 1 eq). The mixture isstirred overnight at room temperature and then poured onto water andextracted with CH₂Cl₂. The combined organic phases are dried over Na₂SO₄and concentrated in vacuo. Flash chromatography or preparative HPLCaffords a compound of formula (I).

General Procedure II—Alkylation:

To a 0.1 M stirred solution of a derivative of general formula (I-1) inDMF is added NaH (60% in oil, 2.1 eq.). After stirring the mixture atroom temperature for 30 min. the electrophilic reactant R¹-hal (1.1 eq.)is added. The mixture is stirred an additional 14 hours at 60 ° C. andthen poured onto water and extracted with ethyl acetate. The combinedorganic phases are dried over Na₂SO₄ and concentrated in vacuo.Purification by preparative HPLC affords the corresponding derivativesof general formula (I-2).

Example 11-[-(6-Methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 6-Methoxy-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 391.5 (M+H⁺).

Example 2 1-[1-(5H-[1,3]Dioxolo[4,5-f]indole-6-carbonyl)-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5H-[1,3]Dioxolo[4,5-f]indole-6-carboxylic acid,    -   ES-MS m/e (%): 405.5 (M+H⁺).

Example 3{5-Bromo-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Bromo-1-cyanomethyl-1H-indole-2-carboxylic acid        (described herein below),    -   ES-MS m/e (%): 478.0 (M+H⁺).

5-Bromo-1-cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 1.0 eq. of 5-Bromo-1-cyanomethyl-1H-indole-2-carboxylicacid ethyl ester (prepared according to U.S. Pat. No. 5,854,245) in amixture of THF/H₂O ((9/1) was added LiOH.H₂O (1.0 eq.) and the reactionmixture stirred 6 h at RT, acidified to pH 2 and then partiallyconcentrated until precipitation of the crude product which was filteredoff and washed with Et₂O and then dried to give the desired product as abeige solid (86%).

-   -   ES-MS m/e (%):=279.0 (M−H⁺).

Example 42-(2-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-isoindole-1,3-dione

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid:        3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-5-methoxy-1H-indole-2-carboxylic        acid,    -   ES-MS m/e (%): 564.5 (M+H⁺).

Example 5N-(1-Methyl-2-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-acetamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-(2-Acetylamino-propyl)-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%):458.6 (M−H⁺).

Example 6N-(2-{5-Methoxy-7-nitro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-acetamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-(2-Acetylamino-propyl)-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 519.6 (M−H⁺).

Example 75-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-7,8-dihydro-1H-pyrano[2,3-g]indol-9-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Methoxy-9-oxo-1,7,8,9-tetrahydro-pyrano        [2,3-g]indole-2-carboxylic acid    -   ES-MS m/e (%): 461.5 (M+H⁺).

Example 84-Fluoro-N-{2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-benzamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-(4-Fluoro-benzoylamino)-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 498.5 (M+H⁺).

Example 92,4,5-Trimethyl-N-{2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-benzamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-(2,4,5-Trimethyl-benzoylamino)-1H-indole-2-carboxylic        acid,    -   ES-MS m/e (%): 522.6 (M+H⁺).

Example 10N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Methoxy-3-(2-nitro-benzoylamino)-1H-indole-2-carboxylic        acid,    -   ES-MS m/e (%): 555.5 (M+H⁺).

Example 11N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-(4-Fluoro-benzoylamino)-5-methyl-1H-indole-2-carboxylic        acid,    -   ES-MS m/e (%): 512.5 (M+H⁺).

Example 12N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid:        5-Methyl-3-(3-trifluoromethyl-benzoylamino)-1H-indole-2-carboxylic        acid,    -   ES-MS m/e (%): 560.6 (M−H⁺).

Example 131-[-(5-Bromo-3-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Bromo-3-methyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 453.4 (M+H⁺).

Example 14{2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-aceticacid ethyl ester

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Ethoxycarbonylmethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 447.5 (M+H⁺).

Example 151-[-(5-Fluoro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Fluoro-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 379.4 (M+H⁺).

Example 161-[-(4-Ethyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4-Ethyl-5-methyl-1H-indole-2-carboxylic acid (prepared        according to DE 2203542)    -   ES-MS m/e (%): 403.5 (M+H⁺).

Example 171-[-(5-Methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Methoxy-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 391.5 (M+H⁺).

Example 181-[1-[(5-Chloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Chloro-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 393.5 (M+H⁺).

Example 191-[-(1H-Indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 1H-Indole-2-carboxylic acid,    -   ES-MS m/e (%): 359.1 (M−H⁺).

Example 201-[-(4-Methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4-Methyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 375.5 (M+H⁺).

Example 211-[-(3-Phenyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Phenyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 437.5 (M+H⁺).

Example 221-[-(1-Methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 1-Methyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 375.5 (M+H⁺).

Example 231-[1-(4,5-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4,5-Dimethyl-1H-indole-2-carboxylic acid (prepared        according to DE 2203542)    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 241-[1-(5-Chloro-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Chloro-4-methyl-1H-indole-2-carboxylic acid (prepared        according to DE 2203542)    -   ES-MS m/e (%): 407.5 (M−H⁺).

Example 251-[-(5-Fluoro-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Fluoro-4-methyl-1H-indole-2-carboxylic acid (prepared        according to DE 2203542)    -   ES-MS m/e (%): 393.5 (M+H⁺).

Example 261-[-(6,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 6,7-Dimethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 271-[-(3-Ethyl-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Ethyl-4-methyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 403.5 (M+H⁺).

Example 281-[-(3-Ethyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Ethyl-5-methyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 403.5 (M+H⁺).

Example 291-[-(3-Ethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Ethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 301-[-(3,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3,7-Dimethyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 311-[-(3,5,7-Trimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3dihydrobenzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3,5,7-Trimethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 403.5 (M+H⁺).

Example 321-[-(5-Bromo-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Bromo-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 439.0 (M+H⁺).

Example 331-[1-(3-Benzyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 3-Benzyl-5-methyl-1H-indole-2-carboxylic acid (prepared        according to Khimiko-Farmatsevticheskii Zhurnal (1969), 3(7),        10-15)    -   ES-MS m/e (%): 463.6 (M−H⁺).

Example 341-[-(5-Methyl-3-phenyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Methyl-3-phenyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 449.5 (M−H⁺).

Example 351-[1-(6-Methoxy-3-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 6-Methoxy-3-methyl-1H-indole-2-carboxylic acid (prepared        according to Journal of Organic Chemistry (1997), 62(26),        9298-9304)    -   ES-MS m/e (%): 405.5 (M+H⁺).

Example 361-[1-(4,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4,7-Dimethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 371-[1-(7-Benzyloxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 7-Benzyloxy-1H-indole-2-carboxylic acid (preparation        described in WO 2004018428)    -   ES-MS m/e (%): 467.6 (M+H⁺).

Example 381-[1-(4-Chloro-5-methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4-Chloro-5-methoxy-1H-indole-2-carboxylic acid        (preparation described in DE 2203542)    -   ES-MS m/e (%): 425.4 (M+H⁺).

Example 391-[1-(5,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5,7-Dimethyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 389.5 (M+H⁺).

Example 401-[1-(4,5-Dichloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 4,5-Dichloro-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 429.4 (M+H⁺).

Example 411-[1-(5-Methoxy-6-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Methoxy-6-methyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 405.5 (M+H⁺).

Example 421-[1-(5-Bromo-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Bromo-4-methyl-1H-indole-2-carboxylic acid (described in        US 2004053979)    -   ES-MS m/e (%): 451.5 (M−H⁺).

Example 431-[-(5-Chloro-1-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Chloro-1-methyl-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 409.1 (M+H⁺).

Example 44{2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 1-Cyanomethyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 400.4 (M+H⁺).

Cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 1.0 eq. of 1-cyanomethyl-1H-indole-2-carboxylic acidethyl ester, in a mixture of THF/H₂O ((9/1) was added LiOH.H₂O (1.0 eq.)and the reaction mixture stirred 6 h at RT, acidified to pH2 and thenpartially concentrated until precipitation of the crude product whichwas filtered off and washed with Et₂O and then dried to give the desiredproduct as a light yellow solid (70%).

-   -   ES-MS m/e (%): 199.0 (M−H⁺).

Example 45{5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid    -   ES-MS m/e (%): 434.1 (M+H⁺).

5-Chloro-1-cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 1.0 eq. of5-chloro-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (preparedaccording to Indian Journal of Chemistry, Section B: Organic ChemistryIncluding Medicinal Chemistry (1989), 28B(12), 1065-8) in a mixture ofTHF/H₂O ((9/1) was added LiOH.H₂O (1.0 eq.) and the reaction mixturestirred 6 h at R/T, acidified to pH2 and then partially concentrateduntil precipitation of the crude product which was filtered off andwashed with Et₂O and then dried to give the desired product as a lightyellow solid (84%).

-   -   ES-MS m/e (%): 232.9 (M−H⁺).

Example 46{5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-7-yl}-acetonitrile

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,    -   Acid: 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid        (described hereinafter),    -   ES-MS m/e (%): 434.3 (M+H⁺).

a) 2-[(4-Chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester

To a stirred solution of 0.55 g (2.85 mmol) of(4-chloro-2-methyl-phenyl)-hydrazine, in acetic acid (5 ml), was added0.34 g (2.91 mmol) of ethyl pyruvate. The mixture was stirred 2 hours at35° C., poured onto an aqueous solution of sat. NaHCO₃ and thenextracted with ethyl acetate. The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo, to afford 0.702 g (97%) of2-[(4-chloro-2-methyl-phenyl)-hydrazonol-propionic acid ethyl ester as alight orange solid.

b) 5-Chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester

To a solution of 0.70 g (2.75 mmol) of2-[(4-chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester in asealed tube was added toluene (10 ml) and amberlyst 15 (1.60 g). Thereaction mixture was heated at 120° C. over the night. The reactionmixture was concentrated under vacuo and purified by flashchromatography (SiO₂, EtOAc/Hex 1/6) to afford 0.22 g (34%) of5-chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester as a whitesolid.

-   -   ES-MS m/e (%): 238.1 (M+H⁺).

c) 5-Chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester

To a solution of 0.22 g (0.9 mmol) of5-chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester in CH₂Cl₂ (10ml), 0.21 g of di-tert-butyl dicarbonate, 0.13 ml of Et₃N and 23 mg ofDMAP were added. The reaction mixture was stirred at RT for 2 hours,poured onto an aqueous solution of HCl 1M and extracted with CH₂Cl₂. Thereaction mixture was concentrated under vacuo and purified by flashchromatography (SiO2, EtOAc/Hex 1/9) to afford 0.30 g (97%) of5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester as a light yellow solid.

d) 7-Bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

To a solution of 0.30 g (0.9 mmol) of5-chloro-7-methyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester in CCl₄ (10 ml), 016 g N-bromosuccinimide (NBS) and 11 mgof benzoyl peroxide were added. The reaction mixture was heated atreflux for one hour and cooled down to RT. The succinimide was filteredoff and the solvent removed under reduced pressure to afford 0.35 g(95%) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid1-tert-butyl ester 2-ethyl ester as a light brown solid. This productwas directly used in the next step (unstable).

e) 5-Chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

To a solution of 1.00 g (2.4 mmol) of7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester in DMSO (10 ml) at RT, 012 g of sodium cyanide was added.The reaction mixture was stirred at RT for one hour, poured on asaturated aqueous ammonium chloride solution and the product wasextracted with EtOAc. The combined organic phases were dried over Na₂SO₄and concentrated in vacuo. Flash chromatography (SiO₂, EtOAc/Hex 9/1)afforded 0.31 g (36%) of 5-chloro-7-cyanomethyl-indole-1,2-dicarboxylicacid 1-tert-butyl ester 2-ethyl ester as a light yellow oil.

f) 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester

To a solution of 0.30 g (0.8 mmol) of5-chloro-7-cyanomethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester in CH₂Cl₂ (8 ml) at RT was added 2 ml of TFA. The reactionmixture was stirred at RT for one hour and concentrated under vacuo Thecrude was taken up in EtOAc and neutralized with aqueous NaHCO3. Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuo. Preparative HPLC (30% CH₃CN/H₂O) afforded 81 mg (35%) of5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester as awhite solid.

g) 5-Chloro-7-cyanomethyl-1H-indole-2-carboxylic acid

To a solution of 81 mg (0.3 mmol) of5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester inTHF/EtOH/H₂O (5 ml) at RT was added 39 mg of LiOH.H₂O. The reactionmixture was stirred at 40° C. for three hours and then acidified withaqueous HCl 1M. The product was extracted with EtOAc and concentratedunder vacuo to afford 71 mg (98%) of5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid as a white solid.ES-MS m/e (%): 232.9 (M−H⁺).

Example 471-[1-(5-Chloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1,3-dihydro-indol-2-one,    -   Acid: 5-Chloro-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 394.4 (M+H⁺).

Example 48(4-Benzotriazol-1-yl-piperidin-1-yl)-(5-chloro-1H-indol-2-yl)-methanone

Amide coupling according to general procedure I:

-   -   Amine: 1-Piperidin-4-yl-1H-benzotriazole,    -   Acid: 5-Chloro-1H-indole-2-carboxylic acid,    -   ES-MS m/e (%): 380.4 (M+H⁺).

1. A compound of formula (Ia)

R¹ is hydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH, or—(C₁₋₆-alkylene)-C(O)-NR^(a)R^(b); R² is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), —(C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R³ ishydrogen, halo, or C₁₋₆-alkyl; R⁴ is hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R⁵is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R⁴ and R⁵ are boundtogether to form a ring with the benzo moiety, wherein —R⁴—R⁵— is—O—(CH₂)_(n)—O— wherein n is 1 or 2; R⁶ is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), —O-benzyl, optionally subsitituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano,—(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to 6-memberedheteroaryl, 4- to 6-membered heterocycloalkyl or 3 to 6-memberedcycloalkyl, each optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or R⁵ and R⁶ are bound together to form a ring with the benzomoiety, wherein —R⁵—R⁶ is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or—O—(CH₂)_(n)—O— wherein n is 1 or 2; R⁷ is hydrogen or C₁₋₆-alkyl; R⁸,R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁ ₆-alkoxy; R^(a), R^(b), R^(i)and R^(j) are each independently hydrogen, C₁₋₆-alkyl,—(C₁₋₆-alkylene)-NR^(k)R^(l), wherein R^(k) and R^(l) are eachindependently hydrogen or C₁₋₆-alkyl, or R^(a) and R^(b), or R^(i) andR^(j) together with the nitrogen to which they are bound form a five orsix membered heterocycle comprising one or two heteroatoms selected fromthe group of nitrogen, oxygen and sulfur; R^(c), R^(d), R^(g) and R^(h)are each independently hydrogen, C₁₋₆-alkyl, —C(O)R^(e), or —S(O)₂R^(e)wherein R^(e) is selected from the group of hydrogen, C₁₋₆-alkyl, andphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R^(c) andR^(d), or R^(g) and R^(h) together with the nitrogen to which they arebound form a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur; orR^(c) and R^(d), or R^(g) and R^(h) together with the nitrogen to whichthey are bound form isoindole-1,3-dione; R^(f) is selected fromhydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy; and phenyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R^(a) and R^(b), R^(c) andR^(d), R^(i) and R^(j), or R^(g) and R^(h) together with the nitrogen towhich they are attached form piperazine, 4-(C₁₋₆-alkyl)-piperazine,4-methylpiperazine, morpholine, piperidine, or pyrrolidine.
 3. Thecompound of claim 1, wherein R^(m) is a 5- or 6-membered heteroarylselected from the group consisting of pyridine, pyrimidine, pyrazine,pyridazine, imidazole, pyrazole, oxazole, and isoxazole.
 4. The compoundof claim 1, wherein R^(m) is a 4- or 6-membered heterocycloalkylselected from the group consisting of pyrrolidine, oxethane,tetrahydropyrane, piperidine, morpholine, and piperazine.
 5. Thecompound of claim 1, wherein R¹ is hydrogen or C₁₋₆-alkyl, optionallysubstituted by CN or OH.
 6. The compound of claim 1, wherein R² ishydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), whereinR^(c) and R^(d) are each independently hydrogen, —C(O)R^(e), or—S(O)₂R^(e)  wherein R^(e) is selected from the group of   hydrogen,  C₁₋₆-alkyl, and   phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano, or R^(c) and R^(d) together with the nitrogen to which they arebound form isoindole-1,3-dione, —(C₁₋₆-alkylene)-C(O)R^(f), whereinR^(f) is selected from hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, and phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; benzyl, optionallysubsitituted by halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl, optionally subsitituted byhalo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro,or cyano.
 7. The compound of claim 1, wherein R³ is hydrogen or halo. 8.The compound of claim 1, wherein R⁴ is hydrogen; halo; C₁₋₆-alkyl; orC₁₋₆-alkoxy; or R⁴ and R⁵ are bound together to form a ring with thebenzo moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or
 2. 9.The compound of claim 1, wherein R⁵ is hydrogen, C₁₋₆-alkyl, orC₁₋₆-alkoxy, or R⁴ and R⁵ are bound together to form a ring with thebenzo moiety, wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2.10. The compound of claim 1, wherein R⁶ is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h) whereinR^(g) and R^(h) are each independently selected from hydrogen andC₁₋₆-alkyl; or wherein R^(g) and R^(h) together with the nitrogen towhich they are bound form a five or six membered heterocycle comprisingone or two heteroatoms selected from the group of nitrogen, oxygen andsulfur; —(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j) wherein R^(i) and R^(j) areeach independently hydrogen; C₁₋₆-alkyl; —(C₁₋₆-alkylene)-NR^(k)R^(l); wherein R^(k) and R^(l) are each independently hydrogen or C₁₋₆-alkyl;or R^(i) and R^(j) together with the nitrogen to which they are boundform a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur;—O-benzyl, optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; nitro; halo;cyano; C₁₋₆-alkoxy; halo-C₁₋₆-alkoxy; halo-C₁₋₆-alkyl;—(C₁₋₆-alkylene)-C(O)R^(f); wherein R^(f) is selected from hydrogen;C₁₋₆-alkyl; C₁₋₆-alkoxy; and phenyl, optionally substituted by one ormore halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy,nitro, or cyano, phenyl, optionally subsitituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; —(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to6-membered heteroaryl, 4- to 6-membered heterocycloalkyl or 3 to6-membered cycloalkyl, each optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or or R⁵ and R⁶ are bound together to form a ring with the benzomoiety, wherein —R⁵—R⁶— is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or—O—(CH₂)_(n)—O— wherein n is 1 or
 2. 11. The compound of claim 1,wherein R⁶ is hydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH,—O-benzyl, optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or nitro; orR⁵ and R⁶ are bound together to form a ring with the benzo moiety,wherein —R⁵—R⁶— is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O— wherein n is 1or 2.,
 12. The compound of claim 1, wherein R⁷ is hydrogen.
 13. Thecompound of claim 1, wherein R⁸, R⁹, R¹⁰, and R¹¹ are hydrogen.
 14. Thecompound of claim 1, wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independentlyhydrogen or halogen.
 15. The compound of claim 1, wherein R⁹ is fluoroand R⁸, R¹⁰, and R¹¹ are hydrogen.
 16. The compound of claim 1, whereinR⁸, R⁹, and R¹¹ are hydrogen, and R¹⁰ is bromo.
 17. The compound ofclaim 1, wherein R⁸, R⁹, R¹⁰, and R¹¹ are each independently hydrogen ormethyl.
 18. The compound of claim 1, wherein R⁸, R⁹, and R¹⁰ arehydrogen and R¹¹ is methyl.
 19. The compound of claim 1, wherein R¹ ishydrogen or C₁₋₆-alkyl, optionally substituted by CN or OH; R² ishydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), whereinR^(c) and R^(d) are each independently hydrogen, —C(O)R^(e), or—S(O)₂R^(e),  wherein R^(e) is selected from   hydrogen,   C₁₋₆-alkyl,and   phenyl, optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or R^(c) and R^(d) together with the nitrogen to which they arebound form isoindole-1,3-dione, —(C₁₋₆-alkylene)-C(O)R^(f), whereinR^(f) is selected from hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, and phenyl,optionally substituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, benzyl, optionallysubsitituted by halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl, optionally subsitituted byhalo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro,or cyano; R³ is hydrogen, halo, or C₁₋₆-alkyl; R⁴ is hydrogen, halo,C₁₋₆-alkyl, or C₁₋₆-alkoxy; R⁵ is hydrogen, C₁₋₆-alkyl, or C₁₋₆-alkoxy;or R⁴ and R⁵ are bound together to form a ring with the benzo moiety,wherein —R⁴—R⁵— is —O—(CH₂)_(n)—O— wherein n is 1 or 2; R⁶ is hydrogen,C₁₋₆-alkyl, optionally substituted by CN or OH, —O-benzyl, optionallysubsitituted by one or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl,C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or nitro; or R⁵ and R⁶are bound together to form a ring with the benzo moiety, wherein —R⁵—R⁶—is —O—(CH₂)_(n)—C(O)—; or —C(O)—(CH₂)_(n)—O— and n is 1 or 2; R⁷ ishydrogen; R⁸, R⁹, R¹⁰, and R¹¹ are each hydrogen.
 20. The compound ofclaim 1, selected from the group consisting of1-[1-(6-Methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5H-[1,3]Dioxolo[4,5-f]indole-6-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;{5-Bromo-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile;2-(2-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-isoindole-1,3-dione;N-(1-Methyl-2-{2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-acetamide;N-(2-{5-Methoxy-7-nitro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-ethyl)-acetamide;5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-7,8-dihydro-1H-pyrano[2,3-g]indol-9-one;4-Fluoro-N-{2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-benzamide;2,4,5-Trimethyl-N-{2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-benzamide;N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide;N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide;N-{5-Methoxy-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-2-nitro-benzamide;1-[1-(5-Bromo-3-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;{2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-3-yl}-aceticacid ethyl ester; and1-[1-(5-Fluoro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one.21. The compound of claim 1, selected from the group consisting of1-[1-(4-Ethyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Chloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[-(1H-Indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(4-Methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(3-Phenyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[-(1-Methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(4,5-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Chloro-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Fluoro-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(6,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(3-Ethyl-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(3-Ethyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(3-Ethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;and1-[1-(3,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one.22. The compound of claim 1, selected from the group consisting of1-[1-(3,5,7-Trimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3dihydrobenzoimidazol-2-one;1-[1-(5-Bromo-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(3-Benzyl-5-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Methyl-3-phenyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(6-Methoxy-3-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[-(4,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(7-Benzyloxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(4-Chloro-5-methoxy-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5,7-Dimethyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(4,5-Dichloro-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Methoxy-6-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Bromo-4-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;1-[1-(5-Chloro-1-methyl-1H-indole-2-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one;{2-[4-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile;{5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile;and{5-Chloro-2-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-1H-indol-7-yl}-acetonitrile.23. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (Ia)

R¹ is hydrogen, C₁₋₆-alkyl, optionally substituted by CN or OH, or—(C₁₋₆-alkylene)-C(O)−NR^(a)R^(b); R² is hydrogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —(C₁₋₆-alkylene)-NR^(c)R^(d), —(C₁₋₆-alkylene)-C(O)R^(f),benzyl, optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano, or phenyl,optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; R³ ishydrogen, halo, or C₁₋₆-alkyl; R⁴ is hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, or —O—C₂₋₁₀-alkenyl; R⁵is hydrogen, halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy; or R⁴ and R⁵ are boundtogether to form a ring with the benzo moiety, wherein —R⁴—R⁵— is—O—(CH₂)_(n)—O— wherein n is 1 or 2; R⁶is hydrogen, C₁₋₆-alkyl,optionally substituted by CN or OH, —(C₁₋₆-alkylene)-NR^(g)R^(h),—(C₁₋₆-alkylene)-C(O)—NR^(i)R^(j), —O-benzyl, optionally subsitituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano, nitro, halo, cyano, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, halo-C₁₋₆-alkyl, —(C₁₋₆-alkylene)-C(O)R^(f), phenyl,optionally subsitituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano,—(C₁₋₃-alkylene)-R^(m), wherein R^(m) is phenyl, a 5- to 6-memberedheteroaryl, 4- to 6-membered heterocycloalkyl or 3 to 6-memberedcycloalkyl, each optionally substituted by one or more halo,halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, orcyano; or R⁵ and R⁶ are bound together to form a ring with the benzomoiety, wherein —R⁵—R⁶— is —O—(CH₂)_(n)—C(O)—, —C(O)—(CH₂)_(n)—O—, or—O—(CH₂)_(n)—O— wherein n is 1 or 2; R⁷ is hydrogen or C₁₋₆-alkyl; R⁸,R⁹, R¹⁰, and R¹¹ are each independently hydrogen, halo, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy or halo-C₁₋₆-alkoxy; R^(a), R^(b), R^(i)and R^(j) are each independently hydrogen, C₁₋₆-alkyl,—(C₁₋₆-alkylene)-NR^(k)R^(l), wherein R^(k) and R^(l) are eachindependently hydrogen or C₁₋₆-alkyl, or R^(a) and R^(b), or R^(i) andR^(j) together with the nitrogen to which they are bound form a five orsix membered heterocycle comprising one or two heteroatoms selected fromthe group of nitrogen, oxygen and sulfur; R^(c), R^(d), R^(g) and R^(h)are each independently hydrogen, C₁₋₆-alkyl, —C(O)R^(e), or —S(O)₂R^(e)wherein R^(e) is selected from the group of hydrogen, C₁₋₆-alkyl, andphenyl, optionally substituted by one or more halo, halo-C₁₋₆-alkyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, halo-C₁₋₆-alkoxy, nitro, or cyano; or R^(c) andR^(d), or R^(g) and R^(h) together with the nitrogen to which they arebound form a five or six membered heterocycle comprising one or twoheteroatoms selected from the group of nitrogen, oxygen and sulfur; orR^(c) and R^(d), or R^(g) and R^(h) together with the nitrogen to whichthey are bound form isoindole-1,3-dione; R^(f) is selected fromhydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy; and phenyl, optionally substituted byone or more halo, halo-C₁₋₆-alkyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,halo-C₁₋₆-alkoxy, nitro, or cyano; or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.